In this application, we propose to continue our on-going studies aimed at understanding the molecular pathogenesis and clinical behavior of DLLC, a clinically important subset of non-Hodgkin's lymphoma (NHL). The proposed studies have two aims. One aim is molecular analysis of a new class of chromosome aberration called promiscuous translocation. Promiscuously rearranging chromosomal sites participate in recurring translocations involving the IGH gene as well as other chromosomal sites suggesting that the candidate genes at these sites may be deregulated either by formation of chimeric gene products or by utilization of unrelated promoters. The following experimental goals will be pursued: (1) To isolate and characterize the candidate deregulated genes at the promiscuously rearranging chromosomal sites 1q21, 12p12, 12q24, and 15q13 through IGH-gene-associated rearrangements. (2). To molecularly characterize the rearrangements at the chromosomal sites which participate in non-14q32-associated translocation subsets involving the promiscuous translocation site 3q27/BCL6. The chromosomal sites targeted for this analysis will compromise: 1q21, 2q21, 4p11, and 5q13. A variety of cloning strategies including those based on IGH gene rearrangement, positional cloning, and identification of novel mRNA species fused 5' of mRNA of known rearranged genes by the RACE technique, will be utilized. The hypothesis underlying these studies is that analysis of normal and deregulated function of genes involved in such translocations will contribute to an understanding of the biology of DLLC. A second aim of this application is to develop a genetic prognostic model for DLLC based on rearrangements affecting deregulated genes, amplification of specific genes, and copy number changes of chromosomal regions determined by the comparative genomic hybridization (CGH) technique. These genetic endpoints will be correlated with established clinical prognostic markers such as cell type and measures of bulk and extent of disease. A retrospective and a prospective analysis will be undertaken, the latter based on patients entered on the MSKCC Lymphoma protocol, NHL15M. The hypothesis underlying these studies is that the genetic basis of clinical outcome is complex and depends not only on deregulation of specific genes, but also on copy number changes of genes and chromosomal regions. The studies outlined will test the hypotheses proposed; they are a logical extension of our previous studies of DLLC and can be expected to lead to a better understanding of the biology and clinical behavior of this disease.